Associative factors in drug pretreatment effects on gustatory conditioning: Cross-drug effects

The pretreatment effect (PE) in gustatory avoidance conditioning refers to the fact that pretreatment with a variety of pharmacological agents subsequently reduces the ability of the same agents to induce gustatory aversion. Explanations of this phenomenon emphasize either tolerance or associative interference. Any explanation of the phenomenon must also account for the present findings which demonstrate the PE when agents of pretreatment and conditioning were pharmacologically dissimilar. Rats were pretreated with d-amphetamine and tested for acquisition of an aversion to saccharin conditioned by amphetamine or morphine. The PE was obtained regardless of the drug used in conditioning. An associative manipulation involving nonreinforced presentation of the drug administration cues (i.e., injections followed by saline instead of drug), that attenuated the PE when pretreatment and conditioning were with amphetamine, was also effective when the pretreatment agent was amphetamine and the conditioning agent was morphine. The findings were interpreted within a framework of compensatory conditioning of a general physiological mechanism common to all gustatory avoidance.     

Parametric investigations of the effects of prior exposure to amphetamine and morphine on conditioned gustatory aversion

Pretreatment by a psychoactive drug can greatly attenuate the conditioning of gustatory avoidance by that drug. Although such findings have been interpreted in terms of tolerance, alternative explantions are possible. In a series of experiments, it was found that pretreatments with morphine or amphetamine massed at 24-h intervals were no more effective in attenuating conditioning than pretreatments spaced at 120-h intervals, but pretreatment with morphine provided more persistent protection against subsequent conditioning by itself than did amphetamine in a comparable previous experiment. The similarity of massed and spaced pretreatment effects can be interpreted without appealing to tolerance as a factor, but the greater persistence of morphine pretreatment implicates tolerance as a mechanism.     

Enhancement of conditioned preference for a place paired with amphetamine produced by blocking the association between place and amphetamine-induced sickness

Rats learn to prefer a place that has been paired with the rewarding effect of amphetamine. Since amphetamine is also known to produce an aversive effect, called here sickness, pairings of a place with amphetamine should produce a place-sickness association as well as the place-reward association that underlies the conditioned place preference. The purpose of the present experiments was to enhance the conditioned place preference produced by place-amphetamine pairings by blocking the place-sickness association. In Experiments 1 and 2, the taste of saccharin was paired with sickness induced by amphetamine or by lithium, respectively. The saccharin taste was presented prior to each pairing of a white chamber with amphetamine to block the place-sickness association. In Experiment 3, a brief placement in a distinctive cage that had previously been paired with lithium-induced sickness preceded each pairing of the white chamber with amphetamine. Blocking of the place-sickness association occurred as evidenced by the reliable enhancement of conditioned place preference obtained in each of the three experiments.     

Neuroleptics block the positive reinforcing effects of amphetamine but not of morphine as measured by place conditioning

The role of dopamine brain systems in mediating the rewarding effects of opiates and stimulants was investigated using the conditioned place preference paradigm. The effects of the neuroleptics alpha-flupentixol (0.8 mg/kg, IP) and haloperidol (1.0 mg/kg, IP) were tested against the place preferences produced by morphine sulphate (1.0 and 5.0 mg/kg, SC), d-amphetamine sulphate (1.0 mg/kg, IP) and cocaine hydrochloride (5.0 mg/kg, IP). Amphetamine place preference was successfully blocked but neuroleptic pretreatment had no effect on the place preferences produced by cocaine and morphine, alpha-Flupentixol alone produced no place conditioning. These results support the hypothesis of dopamine involvement in amphetamine reward. However, morphine reward, as measured by the conditioned place preference paradigm, appears not to be critically dependent on brain dopamine systems.     

Conditioned aversion by amphetamine: Rates of acquisition and loss of the attenuating effects of prior exposure

Chronic prior treatment with amphetamine greatly attenuates the conditioned aversion to saccharin that may be produced by amphetamine. Two experiments were designed to determine some of the limiting conditions of this phenomenon. In Experiment 1, chronic treatment with 7.5 mg/kg of amphetamine was administered for 0, 1, 5, or 20 days prior to pairing saccharin with an injection of 1.0 mg/kg of d-amphetamine sulphate. The results indicated that between 5 and 20 days of treatment were necessary for the treatment to be effective in attenuating conditioned aversion. In Experiment 2, rats were withdrawn from treatment with 20 mg/kg of amphetamine for 1, 7, or 14 days prior to conditioning trials with 1.0 mg/kg of amphetamine. The prior treatment lost its effectiveness in attenuating conditioned aversion between 7 and 14 days after withdrawal. Although alternative explanations are possible, the time intervals required for acquisition and loss of the effectiveness of prior treatment are consistent with the hypothesis that tolerance is the mechanism underlying the observed effects.     

Effects of central and peripheral pretreatment with fluoxetine in gustatory conditioning

The administration of fluoxetine, a relatively specific serotonin uptake inhibitor, an hour prior to a taste-drug pairing was shown to attenuate the acquisition of taste aversions in a dose-dependent manner. Desipramine which is less effective than fluoxetine in blocking the reuptake of serotonin was also less potent in reducing the magnitude of taste aversions. Depletion of forebrain serotonin by lesions of the dorsal and median raphe nuclei or of norepinephrine by lesions of the dorsal noradrenergic bundle failed to prevent the pretreatment effect produced by either fluoxetine or desipramine. Rats with raphe lesions consistently consumed less of the taste paired with lithium than did control animals; however, this decreased intake occurred under both drug and saline pretreatment conditions, suggesting an increased sensitivity to the taste-lithium pairing rather than a diminution of the pretreatment effect. Rats with dorsal bundle lesions failed to differentiate between drug and saline pretreatment, consuming similar amounts under both conditions. These findings as well as the observation that intraventricular administration of fluoxetine did not produce a pretreatment effect suggest that forebrain serotonergic systems are not the critical site of action for the production of pretreatment effects by monoamine uptake inhibitors. Instead, the hypothesis that the peripheral effects of fluoxetine have a stimulus value that acts by way of an associative mechanism to attenuate gustatory conditioning must be considered.     

Role of drug-administration cues in the associative control of morphine tolerance in the rat

This research investigated the role of injection procedures as a potential confound in the study of associative and nonassociative morphine tolerance development. Rats administered a series of morphine injections paired with a distinctive context environment can develop tolerance controlled associatively by the context. However, rats given morphine unpaired with the context may also develop some degree of tolerance. This study examined whether this tolerance represents an associative effect with animals using the injection ritual as a cue predictive of morphine delivery. Following 14 days of habituation to handling and injection stimuli, rats were given eight morphine injections (20 mg/kg, IP) explicitly paired or unpaired with a distinctive context. Animals were then tested for morphine analgesia in the context after either a 30-day rest condition or a 30-day period of daily saline injections. Analgesia was assessed by the tail-flick method, and tolerance was defined as the shift to the right of the dose-response curve of morphine-experienced relative to saline control animals. Paired animals across both retention conditions displayed tolerance, whereas tolerance retention in unpaired animals was observed only in those animals not given saline injections over the 30-day interval. Results support an associative interpretation of tolerance observed in unpaired conditions and suggest that the injection ritual may provide highly salient cues for the support of associative tolerance effects.     

Effects of prior amphetamine exposure on approach strategy in appetitive Pavlovian conditioning in rats

RATIONALE: Pavlovian conditioning with a discrete reward-predictive visual cue can elicit two classes of behaviors: "sign-tracking" (approach toward and contact with the cue) and "goal-tracking" (approach toward the site of reward delivery). Sign-tracking has been proposed to be linked to behavioral disorders involving compulsive reward-seeking, such as addiction. Prior exposure to psychostimulant drugs of abuse can facilitate reward-seeking behaviors through enhancements in incentive salience attribution. Thus, it was predicted that a sensitizing regimen of amphetamine exposure would increase sign-tracking behavior. OBJECTIVE: The purpose of these experiments was to determine how a regimen of exposure to amphetamine affects subsequent sign-tracking behavior. MATERIALS AND METHODS: Male Long-Evans rats were given daily injections of d-amphetamine (2.0 mg/kg) or saline for 5 days, then given a 7-day drug-free period followed by testing in a Pavlovian conditioning task. In experiment 1, rats were presented with a visual cue (simultaneous illumination of a light and extension of a lever) located either to the left or right of a centrally located food trough. One cue (CS+) was always followed by food delivery, whereas the other (CS-) was not. In experiment 2, rats were tested in a nondiscriminative (CS+ only) version of the task. RESULTS: In both experiments, amphetamine-exposed rats showed less sign-tracking and more goal-tracking compared to saline controls. CONCLUSIONS: Contrary to predictions, prior amphetamine exposure decreased sign-tracking and increased goal-tracking behavior. However, these results do support the hypothesis that psychostimulant exposure and incentive sensitization enhance behavior directed toward reward-proximal cues at the expense of reward-distal cues.     

Blockade of conditioned taste aversion by scopolamine and N-methyl scopolamine: associative conditioning,not amnesia

The anticholinergic, scopolamine, consistently disrupts one-trial passive avoidance conditioning but the effects of such drugs on one-trial conditioned taste aversion (CTA) are variable and contradictory. In the present study, treatment of rats with scopolamine impaired the suppression of sucrose intake by post-ingestion administration of lithium chloride (LiCl) in a two-bottle choice test. A similar effect was obtained by using N-methyl scopolamine which penetrates the brain only to a limited degree on acute administration. The blockade of CTA could be prevented in three ways: (i) by exposing the rats to sucrose only on the training day, (ii) by pre-exposing the rats to both sucrose and scopolamine, and (iii) by using a less palatable sucrose/ascorbate mixture. The results demonstrate that the effect of scopolamine on taste aversion is not mediated by the central nervous system, and can be modified by altering the novelty and relative salience of the taste conditioned stimulus. These experiments suggest that conditioned associations between taste and LiCl, and scopolamine and LiCl may underlie the blockade of CTA by scopolamine.     

Contribution of associative and nonassociative processes to the development of morphine tolerance

The contribution of associative and nonassociative processes to the development of tolerance to the analgesic effects of morphine in rats was investigated in two experiments. Associative contingencies were manipulated by administering a series of moderately high morphine doses (20 mg/kg) either explicitly paired or explicitly unpaired with a distinctive context. During distinctive context exposures, animals were placed for 60 min in plastic boxes located in a room adjacent to the colony room. The distinctiveness of this environment was enhanced by the presence of white noise and a pine scent. Nonassociative processes were manipulated by administering the morphine at either a very short (6 h) or relatively long (96 h) interdose-interval (IDI). Analgesia was measured on a tail-flick test. At the 96 h IDI, tolerance, as indexed by shifts in dose-response curves, was controlled primarily by associative processes. Associative control over tolerance at the long IDI was evident at an immediate test (experiment 1) and was retained for a 30 day interval (experiment 2). In contrast, tolerance that developed at the 6 h IDI was not influenced by associative contingencies at the immediate test (experiment 1) and showed no retention over a 30 day interval (experiment 2). These data suggest that tolerance that developed at the short IDI was nonassociative. Overall, the results indicate that conditions conducive to the development of non-associative tolerance disrupt the acquisition of associative tolerance. Hypotheses regarding the absence of associative effects at the short IDI are reviewed. Methodological implications of these results for evaluations of associative and nonassociative morphine tolerance are also discussed.     

Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen

The development of behavioural sensitization is thought to depend on the dose and temporal pattern of drug treatment. Previous studies have shown that two distinct morphine pretreatment regimens cause different long-term neuroadaptations in rat striatum. Therefore, in the present study the ability of these pretreatment regimens to induce long-term behavioural sensitization was investigated. One pretreatment regimen, termed “chronic”, consisted of three daily injections, for 5 days, with escalating doses (10–50 mg/kg) of morphine, and the other, termed “intermittent”, of 14 daily injections with morphine (10 mg/kg). Both intermittent and chronic morphine pretreatment caused sensitization to the locomotor effects of morphine, 3 weeks post-treatment, although the former induced a far greater level of sensitization. Moreover, 3 weeks post-treatment, intermittent, but not chronic, morphine pretreatment induced cross-sensitization to the locomotor stimulant effects of amphetamine. Behavioural sensitization following intermittent morphine pretreatment was clear-cut both 1 day and 3 weeks post-treatment, while after 9 weeks, the locomotor effects of morphine were still slightly augmented. It is concluded that intermittent morphine pretreatment is far more effective in inducing long-term behavioural sensitization than chronic morphine pretreatment. Received: 1 July 1996/Final version: 12 December 1996     

Rating the behavioral effects of amphetamine

A nine point rating scale with a highly standardized protocol for assessing the continuum behavioral effects of amphetamine (e.g. hyperactivity, stereotypy, dyskinetic-reactive effects) in rats is described. Dose-response curves for d- and 1-amphetamine were obtained demonstrating a 4: 1 potency ratio of d- to 1-. The capability of the rating scale to assess antagonism of d-amphetamine by pimozide suggested that this scale may be a useful quantitative measure of neuroleptic activity of drugs.     

The effects of dose and repeated administration on the longer-term hypophagia produced by amphetamine in rats

Rats are hypophagic approximately 1-3 and 13-27 h after receiving amphetamine (2.0 mg/kg). This study examined how these short- and longer-term phases of hypophagia were affected by repeated administration of different amphetamine doses. Throughout eight five-day tests, the rats could lever press for food pellets for 1-hour periods beginning every three hours. On test day 1, the rats were treated with saline, and on test day 3, they were treated with a dose of amphetamine. Across tests, for one group, treatment on day 3 alternated between 0.0 (saline) and 0.5 mg/kg amphetamine; for a second, group treatment on day 3 alternated between 1.0 and 2.0 mg/kg amphetamine; and for a third group, treatment on day 3 was always 1.0 mg/kg amphetamine. The patterns of food intake following day 1 saline and day 3 treatment were compared. Short-term food intake was abolished by 0.5, 1.0, and 2.0 mg/kg amphetamine, and no tolerance was observed to this effect. Longer-term hypophagia was produced by 1.0 and 2.0 but not by 0.5 mg/kg. Tolerance to longer-term hypophagia was seen when 1.0 mg/kg alone was used as the day 3 treatment, but not when 1.0 and 2.0 mg/kg were alternated across tests as the day 3 treatment. Short- and longer-term hypophagia were dissociated by threshold doses for elicitation and by differential tolerance. Occasional receipt of a higher amphetamine dose may sometimes increase the longer-term hypophagia produced by a lower dose.     

A mechanism for the development of tolerance to amphetamine in rats

During chronic administration of 16–32 mg/kg i. p. of dl-amphetamine sulphate in rats tolerance to the drug has been found to develop with regard to hyperthermia, anorexia, increased urinary excretion or noradrenaline and adrenaline, but not to stereotype behaviour and increased motor activity. The hypothesis, that the accumulation of p-hydroxynorephedrine, a metabolite of amphetamine in this species, might be involved in the tolerance to amphetamine as a false transmitter in central and peripheral noradrenaline neurons was tested. Rats were pretreated with p-hydroxyamphetamine, 40 mg/kg i. p. 20 h before the injection of amphetamine, 20 mg/kg i.p. After pretreatment with p-hydroxyamphetamine, which is converted to p-hydroxynorephedrine in central and peripheral NA neurons, the effects of amphetamine on body temperature, and urinary excretion of noradrenaline were decreased, while the increased motor activity, the stereotype behaviour, the anorexia and the urinary adrenaline excretion were unaffected. It is concluded that p-hydroxynorephedrine might be involved in the tolerance to the peripheral but probably not to the central effects of amphetamine.Preliminary reports of parts of the present results have been presented at the 7th Congress of C.I.N.P., Praha, August 1970 and at the second joint meeting of the Scandinavian Society of Biological Psychiatry and the Interdisciplinary Society of Biological Psychiatry, Groningen, The Netherlands, September 1970.     

Sensorimotor gating effects produced by repeated dopamine agonists in a paradigm favoring environmental conditioning

RATIONALE: It is not known whether dopamine agonist-induced disruption of prepulse inhibition (PPI) can be conditioned to the environment, a phenomenon established for dopamine agonist-induced locomotor activation and other behaviors. Furthermore, the literature is contradictory regarding whether PPI disruption, like locomotor activity, can become sensitized after repeated dopamine agonist administration. Differences in methodology (e.g. drug-environment pairing) may have contributed to these contradictory findings. OBJECTIVES: In a series of studies, we investigated whether dopamine agonist-induced disruption of PPI could be conditioned and whether repeated administration of dopamine agonists, in a paradigm favorable to conditioning, would produce sensitization to dopamine agonist-induced disruption of PPI. METHODS: One group of rats were administered subcutaneous apomorphine (0.5 mg/kg) daily for 7 (experiment 1) or 5 (experiment 3) consecutive days contingent with startle testing (in testing rooms, immediately before test sessions). A second group received the same apomorphine dose daily in a manner non-contingent with behavioral testing (in home cages after test sessions). The following day, all rats received vehicle injections contingent with the test environment to assess for environmental conditioning (vehicle challenge day). The next day, all animals received a challenge of apomorphine (0.5 mg/kg) contingent with the test environment to assess the contribution of drug-environment pairing on changes observed in apomorphine-induced disruption of PPI (apmorphine challenge day). PPI was measured immediately after drug injections in the test environment. A separate study (experiment 2) tested amphetamine (3.0 mg/kg) using a similar methodology. In a fourth study, rats were pretreated with haloperidol (1.0 mg/kg) or saline prior to receiving daily apomorphine to see if haloperidol could modify the changes in PPI produced by repeated apomorphine administration. RESULTS: On the vehicle challenge day, PPI exhibited by the rats that received daily apomorphine contingent with the testing environment did not differ from the group that received vehicle contingent with the testing environment. However, animals receiving apomorphine contingent with testing exhibited partial tolerance to its PPI effects during the conditioning period. The PPI exhibited by both groups did not differ significantly on the apomorphine-challenge day. Amphetamine produced a complete tolerance to its PPI effects by day 3. Haloperidol pretreatment blocked the PPI tolerance produced by repeated apomorphine injections. CONCLUSIONS: These results suggest: 1) unlike locomotion, PPI disruption induced by apomorphine cannot be conditioned to the environment; 2) unlike locomotion, repeated adminstration of dopamine agonists produce tolerance, rather than sensitization, to PPI; 3) environmental factors do not seem to be critical for PPI tolerance; and 4) dopamine receptors mediate PPI tolerance to apomorphine.     

Chronic amphetamine: Tolerance and reverse tolerance reflect different behavioral actions of the drug

Chronic administration of amphetamine (AMPH) has been reported to produce tolerance to the drug's behavioral effects in some paradigms (self-stimulation, discriminative stimulus, self-administration) and an enhanced effect or reverse tolerance when other behaviors are monitored (locomotor activity, stereotypy). The present study investigated whether the two phenomena are, in fact, related to the particular behavior monitored or reflect the marked differences in the injection regimens (1X vs. 3X daily injections) used to produce the phenomena. The effects of chronic AMPH administered once or three times daily on AMPH facilitation of self-stimulation responding and on the locomotor stimulant and stereotypy-producing effects of the drug were assessed. Regardless of the injection regimen used, chronic AMPH resulted in an enhancement of the locomotor stimulant effects of the drug as well as a more rapid onset and greater intensity of the stereotypy produced. In the self-stimulation paradigm, only the 3X daily regimen significantly reduced the effectiveness of a challenge dose of AMPH (tolerance), although the 1X regimen produced effects that were qualitatively similar but quantitatively less. Perhaps behavioral tasks in which tolerance develops reflect the mood-altering properties of the drug in humans whereas a process similar to reverse tolerance may underlie the increased susceptibility to psychoses elicited by the drug with repeated use.     

Tolerance and cross-tolerance to the effects of amphetamine, methamphetamine and fenfluramine on milk consumption in the rat.

It has been reported that rats develop tolerance to the milk intake suppressant effects of d-amphetamine, d-methamphetamine, and d, l-fenfluramine. However, it has been hypothesized that the mechanism of action of fenfluramine is different from that of the other two drugs. In the present experiment, rats were given one of these 3 phenylethylamine derivatives each day until tolerance developed to the suppression of milk intake. A second of these drug s was then substituted and milk intake measured. There was cross-tolerance to the drug-induced suppression between d-amphetamine and d-methamphetamine, but not between d-amphetamine and d,l-fenfluramine. The lack of cross tolerance suggests a different mechanism of action for these drugs.     

Control of learned conditioned-avoidance responses (CAR) by amphetamine and chlorpromazine

Summary In mice, marked decrement in response strength occurred when conditioned avoidance responses were acquired under amphetamine but emitted without amphetamine or under chlorpromazine; or acquired under chlorpromazine and emitted without chlorpromazine or under amphetamine.     

The effects of amphetamine on maze learning by goldfish

Goldfish performed a simple left-right discrimination in a Y-maze under the influence of amphetamine. The subjects showed facilitation of learning at a low dose (1.25 mg/l) but not at 2.0 mg/l.     

Facilitation of instrumental avoidance learning by amphetamine: An analysis

Summary d-Amphetamine sulfate (1 mg/kg) was studied for its effect on acquisition (learning) of a conditioned avoidance response. Acquisition consisted of a single session of 700 trials in a Skinner box. A light and a noise (CS—conditioned stimulus) were presented for 15 sec ending in a brief shock (UCS—unconditioned stimulus) thus completing one trial. Avoidance responses, incorrect responses (when the CS was off) and wrong lever responses were recorded in blocks of 50 trials. The increase in the somatic motor activity (SMA) after amphetamine in different animals was also measured.Amphetamine significantly increased the rate and level of learning. The drug also caused an increase in incorrect and wrong lever responses. Increase in the wrong lever responses was concomitant with the increase in SMA. The increase in SMA and wrong lever responses subsided although the increase in avoidance responses was maintained.